A facile access to substituted indeno[1,7-bc]furans

00404020193 S6.oQt.W PergammlPressLtd

TetrahedronVol 49, No. 44, pi 9987-9994.1993 Pmted m Great Bntain

A Facile Access to Substituted Indeno[l,7=bc]furans

Karl-Helm

Pfoertnera*,

Gerhard

Englertb

and

Peter

Schoenholzerb

Pharma Diwsion, Preclinical Researcha and New Technologie&, F Hoffmann-La Roche

Ltd,

CH-4002 Easel, Switzerland

(Received in Germany 29 June 1993; accepted 31 August 1993)

Key Words’ 4-oxo-plonone, HCN addibon, mdeno[l,7-bclfurans

Abstrsct:

The reaction of 4-oxo+ronone

1 with 2 eq. HCN from NaCN m MeOH leads m excellent yield

stereospecdically to a ors-fused tncw/ic rmg system of the mdeno[l,7-bc]furan type 5. Acid catalyzed h@olysis of the aminogtvup In 5 gtves factone 5a which was usad to determrne the basic structure of the new mdeno[l,7-bc]fUans by Xray analysrs. The new compounds were fully charactedzed by 1~ and t3C NAM and the assignments supported by NOE (5a) and ‘H-detected one-bond and multipfe-bond tH, 13C-COSY (6&c).

INTRODUCTION Tncyckc preparation between

lactones

of the mdeno[l,7-bclfuran-2-one

of 11 -deoxyprostanords oxygenated

cycloaddrtron

drenes

of 5-substrtuted

and

type are useful

11 -oxosteroids.

and attached

butenolides

2-ethenylcyclopentenes

burldtng

Intramolecular make

them

available1

wtth N-phenylmaleimrde

RESULTS The novel reaction

route

proceeding

accessrble appropriate

to angularly

AND

methylated

from (E)-4_oxo-g-ronone

(E)-p-ronor&,

2-(diazoacyl)furan‘t.

stirred at room temperature

Together

We now report

DISCUSSION

indeno[l,7-bclfuran-Panes tetraacetate

catalyzed

starts with a one-pot by oxidation

intramolecular

with 2 eq. NaCN a methanolrc

to give the cyclic iminoester

9987

Intermolecular

tricyclrc nng system

1 which can be obtained

or by a dirhodium

for the

reactions

and rearrangement

of the resultmg products on srlica gel IS another entry into this class of compounds2 on a much more effortless approach to that as-fused

blocks

Drels-Alder

solution

5 in yrelds up to about 90%.

of industrially reaction

of an

of 1 is simply

K.-H. PFOERTNERer al.

9988

Although reactton

we drd not succeed in trapping

to proceed

via the sequence

HCN to 1 leads to 2 Then the formation bears the cyano consequence cyano

group.

Addition

of the ring closure

group at C(7) is attacked

compounds

in Scheme

of any intermediate, 1 Accordingly,

of 3 IS initiated by deprotonation

of a further

HCN molecule

IS now an isolated

by the hydroxyl

5 and 6b-c were elucidated

IR, see experimental

and Identifying

presented

4

Finally,

methods

X-ray diffraction

(1H, 1%

and complete

analysrs of the tricyclrc lactone 6a (Rg. 2) that was derived from 5 by acid catalyzed

Scheme Preparation

of the racemic (E/Z)-imine

conditions

consequence possibility

appearance

discussion

5 v/e the proposed

of the stereospecific

tn 4 the of

NMR, MS,

spectroscopic hydrolyses.

1 intermediates

2, 3 and 4. Reagents

i, NaCN, ii, MeO- and /or CN-, iii, NaCN, room temperature

A more detailed intermediate

of

of 2 at the C-atom whrch

atom 1 to form 5 The structures

by means of spectroscopic

part) basing on a single-crystal

addrtion

to the keto group of 3, which as a

one, gives cyanohydrin

at carbon

we suggest the

Michael

formation

and

Solvent. MeOH

of 5 has to consider

that the

of 3 with methyl groups at C-atoms 1 and 7a in CIS positron seems to be a

of the thermodynamically

to form a hydrogen-bridge

preferred

chair form of the six-membered

between the lu-hydroxy

ring including

and the 7-0~0 group (Fig 1)

the

9989

Substituted indeno[ 1,7-bc]furans

Figure After formation the la-hydroxyl

1. Sterical

of the cyanohydrin

arrangement

4 only the 7-cyano group in a-position

to give 5. Because the addition of HCN to carbonyl

ring closure of (7a-cyano)-4

to 5 removes this stereoisomer

with its counterpart

a 79-cyano

gave 6a, whereas the carboxylic

of 3

bearing stepwise

hydrolysis

acid 6c (experimental

of the 6carbonitrile

part). Noteworthy

under strong acidic or basic conditions

groups is a reversible

of 4 continuously

group. Acid catalyzed

can be attacked

hydrolysis

by

reaction,

from the equilibrium

of the imino group in 5

of 6a led to the carboxamide

6b and to

is the stability of the lactone ring which even

could not be opened

hydrolytically.

HO

6 Figure 2. Structure of the racemic lactone 6 6a, R = CN; 6b, R = CONH2; 6c, R = COOH

EXPERIMENTAL

PART

General M.p.‘s were measured were obtained

on a Buchi SMP-20 in open capillaries

in KBr with a Nicolet FDlR 719. tH-NMR

at 100.6 MHz were recorded 3000 computer,

on a AM-400 Bruker-Spectrospin

pulse programmer

and are uncorrected.

IR Spectra

spectra at 400 MHz and t3C-NMR Ff-NMR

and 160 Mbyte disk. Solutions

spectrometer

spectra

With Aspect

in 12H61DMS0 with MeqSi as

9990

K.-H. PFOERTNER er al.

Internal standard determmed Impact)

were studied

All couplrng constant

on a AEI MS-9 updated

All new compounds

values J are gtven rn Hz Mass spectra were

with a ZAB console

and data system 3000 (70 eV, Electron

are racemates

Mater/a/s A sample of 4-oxo-8-ronone recrystallized obtained

1 was krndly provided by our vitamrn research department

twice from hexane

at -10” C, m.p

52 - 53 5°C

NaCN pa

It was

and MeOH p a were

from Merck.

Syntheses

2,2a,3,4,5,7,7a,7b-Octahydro-2aS_hydroxy-2-imino-5,5,7a~,7b~-tetramethylindeno~ [1,7-bclfuran-6-carbonitrile

(5)5

NaCN (38.2 g, 0 78 mol) was added to a solution of 1 (80 0 g, 0.388 mol) In MeOH (800 ml) and stirred under N2 for 24 h at room temperature filtered

The precipitate

g, 86.5%, m.p. 230°C). Recrystallization H,7.83, N,ll.l

The brown solution

was chilled to 10°C and

was washed wrth 150 ml MeOH and twice with 150 ml H20 to yield 5 (87 3

Cl5H2ON202

C,69 47,

from MeOH rarsed the m p. to 236°C. (Found

requires C,69.2, H,7.74, N,l0.76%)

IR Ymaxlcm-l

3258 (NH), 3103

(OH), 2218 (con] CN), 1678 (C&N) The imine 5 existed as a 2 135 and no 2D experiments

to 6a-c. The following

analogy

1 mixture of (E/Z) isomers with unknown assignment

were performed

main and minor isomer. lH-NMR

and thus the assignments

assignments

consider

Only DEPT-

of 1H and 13C are given In

both isomers and are given in the order of

6 1 122 , 1 108 (3 H, 2s, 7b6-Me),

1 177, 1.163 (3 H, 2s 5-Me),

1.232, 1.052 (lH, t x d, J - 13.5, 4, 4a-H), 1.341 (3 H, s, 5-Me), 1.381 (3 H, s, 7a8-Me) 1 469 (1 H, d x t, J 14, 3 7, 48-H)

1,801, 1 837 (1 H, t x d, J - 13 7, 4,3a-H), 2 000 (1 H, d x t, J -13 7, 3 5, 36-H)

2 569, 2 612 (1 H, 2d, J 17, 7-H), 2 861 (1 H, d, J 17, 7-H), 5 761, 5 735 (1 H, 2s OH, exchanges with D20), (7a6-Me),

7 594 (1 H, s, NH, exchanges

with D20)

13C-NMR

6 14 50, 14 61 (7b6-Me),

20 79

25.98, 25 92 (5-Me), 27 65, 27 50 (3-C), 29 90. 29.79 (5-Me), 36.03 (5-C), 37 28, 37 13

(4-C), 44.70, 44 67 (7-C), 60.54, 60 30 (7a-C), 77.21, 77 60 (2a-C), 92 10, 91 60 (7b-C), 102 63, 102 89 (6-C), 117 21 (CN), 169 37, 169 67, 170 03, 174 93 (2-C and 5a-C) 2.8%)

217 (13,), 216 (9), 203(15), 202 (100)

199 (15)

161 (14)

MS

m/z

160 (24), 158 (18)

(39) 132 (14) 97 (28) 91 (12) 85 (17) 83 (26) 81 (13) 71 (28) 69 (40) 67 (lo),

260 (M+,

146 (23)

142

55 (55) 45 (11)

43 (74) 41 (45) 39 (29) 29 (24)

2,2a,3,4,5,7a,7b-Octahydro-2aS-hydroxy-5,5,7a~,7b~-tetramethyl-2-oxoindeno~ [1,7-bclfuran-6-carbonitrile

(6a)

A solution of 5 (63 5 g, 0 24 mol) in HCI (25%. 2 5 I) was stirred for 24 h at 60” C After having reduced the solution to 800 ml it was chrlled to 0” - 3°C and filtered times with water to give crude 6a (59.5 g, 93%). Recrystallizatron to 218”

- 219°C

N,5 36%) vmax/cm-’

(Found

C68.82,

H,7 59, N,5.51.

Cl5

The solid was washed several

from 2-propanone

HlgN03

requires

3461 (OH), 2221 (con] CN), 1767 (5-ring lactone C=O)

raised the m p C68 94, H,733,

9991

Substituted indeno[l,7-bclfurans

1H and experiments,

of 6a (4 mg) were

13C assignments DEPT-135,

1H-detected

one-bond

acqursrtion (1JCH = 140 Hz, 300 experiments, range

E of Lrt 6) lmks carbons

version7

reveals

neighbounng carbon

connectrvities

carbons

signals

These

and provide

via

two-

important

and

allow

structural

MHz

1D NOE difference

attached

three-bond

protons, couplings

an unambrguous informatron

during

time) and ‘H-detected

10 h) The one-bond

and their directly

experiments

on 400

COSY with 13C GARP decoupling

2.5 h total accumulation

COSY (JCH = 7 Hz, 300 experiments,

hetero

sequence

based

hetero

hetero

whereas

COSY (pulse the long-range

between

assignment

Some relevant

long-

protons

and

of the proton

and

results are given

as

follows The two geminal peaks between between

methyl

groups

at 5-C were

identified

by corresponding

three-bond

the protons of each group and the carbon of the other one. Moreover,

the same protons and those of a further methyl group (at 7b-C) and carbon 5a-C helped to

identify the latter methyl group. The protons of the remamrng peaks with 7a-C, 7b-C and 7-C as expected

methyl group at 7a-C showed cross

The carbon atoms 4-C and 3-C were drstmgurshed by

cross peaks of the former to the protons of both 5-C methyl groups. Stereospecific these

cross

cross peaks

two

subsequent

geminal

methyl

groups

was

posssrble

by

linking of the 1H signals to the correspondrng

NMR 6 1 058 (1 H, t x d, J -13.5, 4 3, 4*-H),

1D NOE

difference

assignment

experiments

13C shifts via one-bond

correlatron

of and If-f-

1 156 (3 H, s, 7bp-Me), 1 182 (3 H, s, 5a-Me),1 360 (3

H, s, 56-Me), 1 448 (3 H, s, 7af+Me), 1 554 (1 H, d x t, J 14, 4, 4fi-H), 1 835 (1 H, t x d, J 14, 4 5, 3aH), 1 931 (1 H, d x t, J 14 4, 4, 36-H) 2 684 (1 H, d, J 17.3 gem 76-H), 2 970 (1 H, d, J 17.3 gem 7aH), 6 324 ( 1 H, s, OH) Relevant

1D NOE difference

lrradlattonat

results

Enhancemen&!&)

7a-Me

(1 448 ppm)

7b-Me

-/b-Me

(1 156 ppm)

7a-Me

5P-Me

(1 360 ppm)

%-Me

5u-Me

(1,182 ppm)

5f3-Me

13C-NMR: b 13.97 (7b-Me), C), 36 78 (4-C) 16887

(5a-C),

160 (lo),

2 2, >O,

76-H 76-H

2 5, >O,

20 56 (7af+Me),

5 8,

OH

25

2 5,

OH

38

4$-H

2.9

4cr-H

>O

3cr-H

5,

25 64 (Su-Me), 26 57 (3-C), 29 58 (56-Me), 35.98 (5-

44 03 (7-C), 59 37 (7b-C), 76 40 (2a-C), 92 46 (7a-C),103.26 17539

(2-C)

MS m/z

217 (19, M- CO2), 202 (loo),

158 (15),146 (22),144 (17),133 (12)

(50), 41(25), 39 (13) 29 (13)

(6-C), 116.87 (CN),

199 (20), 184 (11)

lSl(ll),

131 (16) 91(10), 77(11), 69 (15) 57(15), 55 (33) 43

K.-H. PFOERTNER~C al.

9992

X-Ray Crystallographic

Structure

Determmatron

of 68.

Crystal size 0.25 x 0.35 x 0 35 mm3 Data were collected on a Nrcolet R3m four circle drffractometer fitted with a graphite monochromator and the LTl cooling apparatus

Scan mode

omega, scan speed 0.8” min-1 , minimum speed Strong reflections were measured up to 10.2” mm-t, scan width 0.9“ 28 range 0 - 50”. Peak-background ratio 5 1. Total reflections observed. 1877, rejectron cntenon I > 2,5a(f). Structure determmation and refinement

The structure was

determined by direct methods usmg SHELXTL-88 system. Refinement proceeded smoothly to convergence at R = 0.040 wrth anrsotropic refmement of all non-H-atoms. Weights w = l/a2(F) + 0 001 IF12 8 Crystal data Cl5Hl~N03, M = 281 32, Monoclmrc, space group P2t/n, a = 8 080(4), b = 10.655(4), c = 15492(6) 1, p = 98.13(3), 2 = 4, D = 1 288 g cm-3, p(Mo-K,) = 0.9 mm-l, F(OO0) 560, h = 0 071069 8, T = 190 K

..:. . B Figure 3 Projection of 6a.

2,2a,3,4,5,7,7a,7b-Octahydro-2aS_hydroxy-5,5,7a~,7b~-tetramethyl-2-oxoindeno~ [1,7-bclfuran-6-carboxamlde

(6b)

To a solution of 6a (25 g, 96 mmol) in MeOH (275 ml) and aq. NaOH(140 ml, 6 mol dm-3) H202 (77.5 ml, 0.88 mol dm3) was added dropwrse during 3 h at ca 40°C After further 2 h stirring the solution was chilled to ca. 3°C and filtered The solid was washed several times with water to yield crude 6b (23.48 g, 88%, m.p. 259°C from dichloromethane) Recrystallization from water gave 6b x H20, m.p 263” - 264°C (Found G64.0, H,8 14, N ,5 0 Ct5H2tN04 x H20 requires C64.03; H,8.24; N,4.98%) Spectroscopic data are given for anhydrous 6b IR vma&m-1 (NHd, 1749 (5-ring lactone GO), 1645 (amide GO)

3386

9993

Substituted indeno[l,7-bc]furans

The assignments detected

one-bond

of the 1H and 13C spectra

(300 expenments,

h) Since no NOE experiments

of 6b (4 mg) were based on DEPT-135,

2.5 h) and long-range

were performed,

lH,

an unambiguous

geminal methyl groups at 5-C was not possible

13C COSY (300 expenments, stereospecific

assignment

lo10

of the

6 1 011 (1 H, t x d, J 14, 4, 4a-H), 1 113

lH-NMR

(3 H, s, 7b@Me), 1 130 and 1 150 (2 x 3H, 2s 2 x 5-Me), 1 387 (1 H, d x t, J 14, 4,46-H),

1 416 (3 H,

s, 7a@Me), 1 750 (1 H, t x d, J 14, 4, 3a-H), 1 875 (1 H, d x t, J 14, 4, 36-H) 2 61 and 2 65 (2 H, ABSpectrum,

J 17 5, 7-H). 6 003 (1 H, s, OH), 7 149 and 7 492 (2 H, 2s NH2)

(7a6-Me),

21 05 (7b6-Me),

25 81 (5-Me),

13C-NMR

6 14 66

26 95 (3-C), 28 77 ( 5-Me), 34 46 (5-C), 37 70 ( 4-C),

45 17 ( 7-C) 56.66 (7b-C), 76.45 (2a-C), 92 57 (7a-C), 129 96 (6-C), 146 16 (5a-C), 170 61 (amrdeC), 176 27 (2-C) MS mh (45)

279 (23, M - H20), 235 (27) 220 (47) 218 (38) 207 (14) 203 (25) 177

175 (25) 162(43), 147(36), 135 (34)

133 (60). 121 (27) 119 (59)

105 (23) 91 (40), 83 (12)

79 (23) 77 (30) 69 (29) 57 (19) 55 (52) 53 (19) 44 (29) 43 (100) 41 (56) 39 (23) 2,2a,3,4,5,7a,7b-Octahydro-2ae_hydroxy-5,5,7a~,7b~-tetramethyi-2-oxoindeno~ [1,7-bclfuran-6-carboxylic

acid

(6~)

To a solution of 6b (1 0 g, 3 36 mmol) in HCI (cone , 25 ml) an aq solution of NaN02

(2 469,

35 7 mmol) was added dropwrse during 1 h at 20°C The reaction mixture was then stirred for 4 5 h at 70°C

Chillrng,

(Found

C,64 Ii’,

filtratron

and washing

H, 7 23, Cl5H2005

iactone C=O), 1701 (carboxylrc

Analogously

with water yrelded requires

t x d, J 14, 4, 4a-H),

m p 217”- 218°C

IR vmaxlcm-’

1733 (5-ring

acrd C=O)

to 6b the assrgnments

range hetero COSY applying

6c (0 79 g, 79%)

C,64 27, H,7 19%)

of 6c were

the same experimental

based on DEPT-135,

conditions

one-bond

as with 6b. lH-NMR:

and long-

b 1 047 (1 H,

1 123 (2 x 3H, s, 2 x 5-Me), 1 153 (3 H, s, 7bf3-Me), 1 420 (3 H, s, 7a@Me),

1 505 (1 H, d x t, J 14, 4, 46-H) 1 775 (1 H, t x d, J _ 13 5, 4, 3a-H), 1.890 (1 H, d x t, 14, 4 6, 36-H) 2 640 (1 H, d, 17 3, 7-H), 2 780 (1 H, d, 17 3, 7-H), 6 083 (1 H, s, 2a-OH), 12 800(1 H, s, HOCC) ‘3C-NMR

b 14 48 (7b@Me), 20 75 (7a6-Me),

25.98 (5-Me), 27 16 (3-C), 28 31 ( 5-Me), 34 32 (5-

0, 37 04 (4-C), 44 51 (7-C), 59 08 (7b-C), 75 99 (2a-C), 92 36 (7a-C), 126 75 (6-C), 150 83 (5a-C), 16937 (COOH), 176 13 (2-C) MS mh 279 (M+, 2%), 236 (M - C02, 34) 222 (12) 221 (89) 218 (23) 203 (34) 175 (23)

162 (29) 147 (32) 135 (23) 133 (47) 119 (20) 107 (14) 97 (23) 91 (26)

83 (23) 77 (18) 71 (24) 69 (48) 67 (13) 57 (44) 55 (55) 43 (100) 41 (54) 39 (17) 29 (25)

ACKNOWLEDGEMENT The authors

thank Mr S Doppler

for expenmental

W Arnold and Mr Ph. Cron (NMR), Mr W. Meister (elemental

analyses)

are gratefully

acknowledged

assistence

Valuable

(MS), Dr. M. Grosjean

contributions

of Dr

(IR) and Mr. G. Nern

K.-H. PFOERTNER et al.

9994

REFERENCES

AND

NOTES

1

Burke, S D ; Magmn, D R , Opllnger, J A , Julia, J P , Abdelmagld, 25, 19.

2

hsher,

3

Becker, E., Albrecht, R , Bernhard, K , Leuenberger,

M J., Hehre, W J , Kahn, S D , Overman,

Schiip, W , Wagner, H P He/v 4

Wenkert, E , Decorzant,

5

Optimized

procedure

Chum. Ada

A Tetrahedron

Lett 1984,

L E. J. Am. Chem. Sot. 1988, 770, 4625 H G W.; Mayer, H.; Muller, R K.;

1981, 64, 2419 and literature

cited herein.

R , Naef, F He/v Chim Acta 1989, 72, 756

Substltutfon of NaCN by KCN or addition of water lowers the yield of

5, which also depends on the starting concentration

of 1 given in brackets

67.4% (0.97 mol

dm-3), 76.7% (0.65 mol dm-3), 86 5% (0.48 mol dm-3), 79 4% (0.32 mol dm-3) 6

Otting, G , Wiithrich, K J Magn Reson. 1988, 76, 569

7

Bax, A, Summers, M J Am Chem

8

Sheldrick, G M , University been deposited Cambridge

Sot

1986, 708, 2093

of Goettlngen,

FRG Coordinates

at the Crystallographic

CB2 lEW, UK

and thermal parameters

Data Centre, Cambndge,

Umversity

Chemical

have Lab,